FDA regulations requires that a contact lens be sterilized upon removal from an eye and before replacement in an eye. Soft contact lenses may be sterilized by one of two methods. The first method is the use of heat sterilization. Heat sterilization consists of boiling soft contact lenses in a saline solution for a period of about 45-50 minutes. The wearer may then remove the lens directly from the saline environment and place the contact lens in the eye.
Cold sterilization consists of disinfecting the contact lens in the absence of heat using a sterilizing solution containing a disinfectant which chemically sterilizes the contact lens. Commercially available cold sterilization systems for contact lenses have two major problems: they irritate the eye to some extent and they require an inconvenient amount of time to work, usually about four hours. The most commonly used active component of cold sterilization systems today is chlorhexidine which can be toxic and irritating to the user even after rinsing the lens.
The art has long sought a method of disinfecting a contact lens in the absence of heat; a method not based on the use of chlorhexidine; a method which is non-toxic and non-irritating to the eye; a method which will use a single solution; a method which works rapidly; a method simple to use; a method easy to convey; a method easy to store.
Hydrogen peroxide has been used in the past for disinfecting contact lenses but has been largely discarded because of the irritation it causes to the eye. This irritation is due to the high concentration of hydrogen peroxide required to be even minimally effective. We believe that high concentrations of hydrogen peroxide are required in conventional systems due to the slow rate at which bactericidal components are generated from hydrogen peroxide. The present invention uses a catalyzed system supplied in powder or pill form which continuously generates bactericidal free radicals over a controlled time period when dissolved in an aqueous carrier.
The present invention uses a peroxide based system in a non-reacting dry state which is activated by the user to form a bactericide having a limited period of bacteriological activity with the bactericide including a peroxide, a peroxidase and a source of donor molecules capable of acting as a substrate for the peroxidase. The present invention overcomes the most obvious objection to the use of hydrogen peroxide alone since the concentration of peroxide in this system is several orders of magnitude less than that used in the prior art and careful formulation of the proportion of the components of the bactericide results in the consumption of a substantial percentage of the peroxide initially exposed to the lens. The present invention results in a concentration of peroxide so low as to cause no irritation to the eye and therefore suits the criteria of an ideal clinical product.
Hydrogen peroxide dissociates into free radicals which are known to be bactericidal. The rate at which free radical species are generated from the uncatalyzed decomposition of hydrogen peroxide determines the bactericidal efficacy of this compound. Enzyme catalyzed reactions are known to occur 10.sup.10 to 10.sup.15 times as rapidly as the corresponding non-enzymatic reactions. In accordance with the present invention an enzyme, peroxidase, has been selected to catalyze the reduction of hydrogen peroxide for generating free radicals. The enzyme peroxidase catalyzes the transfer of electrons from donor molecules to acceptor molecules, peroxides. When an electron is removed from a donor molecule, this molecule is transformed into a bactericidal free radical. The free radicals generated in this process are generated at greatly elevated rates relative to the rate at which free radicals are generated from the non-enzymatic dissociation of peroxide. The present invention allows for the sterilization of a contact lens in minutes instead of hours and therefore better suits the criteria of an ideal clinical product.
Peroxidases are classified as enzymes which act to reduce hydrogen peroxide. The different types of peroxidases are distinguished by the donor molecules they use; donor molecules supply electrons which peroxidase donates to hydrogen peroxide. In accordance with the present invention a peroxidase is used to generate free radicals from donor molecules. The donor molecules must be capable of acting as a substrate for peroxidase in generating such free radicals. The method of the present invention teaches a practical means to control the generation of free radical species from a bactericide having a limited period of bacteriological activity. The bactericide of the present invention is formed by combining three components, viz., a peroxide, a peroxidase and a source of donor molecules. The bactericide will continuously generate free radicals over a defined period of time depending upon the concentration level of each component in the bactericide.
The duration of free radical production and the amount of free radicals produced can be controlled by careful formulation of the three components comprising the system. As long as the enzymatic reduction of hydrogen peroxide continues, free radicals will be generated. The free radicals being generated have an extremely short lifetime and as such must be continuously generated to prolong the period of bacteriological activity. The duration of the reaction, and therefore it bactericidal lifetime, is controlled via the formulation. Other factors remaining constant, the longer the reaction occurs the greater the bactericidal effectiveness.
The method of the present invention teaches how to maintain the bactericide in a nonreacting state; how to activate the bactericide at the critical moment when sterilization of the contact lens is desired and how to control the generation of free radicals over a preselected time period to complete the sterilization of the lens using a minimum concentration of each component so as not to result in eye irritation. Integral to the success of the invention is the subject of patient compliance in the use of the invention. Given a product which requires admixture of several components at different concentrations, it is assumed by industry that patient compliance and therefore successful use of such a product will be low. Therefore, of critical importance to the present invention is storage of the bactericide in a nonreacting state and preferably in powder or pill form so as to activate the bactericide in a liquid carrier simultaneously with the immersion on the contact lens. Inherent in the powder or pill composition is ease of storage, ease of use and a high level of patient compliance which suit the criteria for an ideal clinical product. In fact, it is only via the formulation of these components in a powder or pill which allows feasibility of this approach for contact lens sterilzation.
The concentration and nature of donor molecules in the bactericide is of paramount importance since the donor molecules or products thereof are transformed in the reaction into the bactericidal agents; the reaction of the donor molecules with the enzyme is the slowest step in the reaction mechanism. Many donor molecules may be used either alone or in combination with other donor molecules. Some donor molecules are preferred substrates relative to the type of peroxidase selected, and within such a group of donor molecules some are preferred due to interactions that donor molecules may have with bacteria or the surrounding matrix which will enhance or detract from their bactericidal activity. Some donor molecules will be effective against only a limited number of bacterial strains while other donor molecules will exert broader bactericidal efficacy. Some donor molecules will be effective against only comparatively low concentrations of bacteria while other donor molecules will exert bactericidal action over a large range of bacterial concentrations.
The present invention incorporates a peroxide, a peroxidase, and donor molecules which are readily available, inexpensive and easily incorporated into a powder or pill form and therefore suits the criteria of an ideal clinical product. It has been discovered in accordance with the present invention that a minimum concentration level of donor molecules exists below which the bactericide is ineffective for disinfecting a contact lens i.e., the rate of free radical production is too low to be characterized as having any noticeable bactericidal effectiveness. This minimum level for the donor molecule is at least 1.0.times.10.sup.-7 molar. The minimum amount of peroxidase to achieve noticeable bactericidal effectiveness is 0.38.times.10.sup.-3 units per ml; for hydrogen peroxide the minimum concentration level to achieve noticeable bactericidal effectiveness is 1.times.10.sup.-7 molar.
The minimum concentration levels for effective bactericidal action are critically important to the invention since a critical aspect of sterilization solutions is the irritation caused to certain users. Hydrogen peroxide is recognized to be an eye irritant. The level of peroxide left exposed to the lens after the reaction has occurred can be controlled by carefully selecting the initial concentration of the three components and the time for which the reaction will occur. It is important to this invention that the concentrations of the three components be carefully selected to cause most of the peroxide initially exposed to the contact lens to be consumed during the reaction thus reducing the possibility for irritation. That is, the components can be formulated so that the concentration of hydrogen peroxide limits the duration and rate of the generation of free radicals. When this is done it allows for a dramatic depletion of the initial concentration of hydrogen peroxide over the concentration initially exposed to the contact lens. This type of formulation is achieved by insuring that the concentration of donor molecule is large enough so that its concentration does not influence the rate of the generation of free radicals and that the concentration of peroxidase is large enough to reduce all of the hydrogen peroxide which is thermodynamically capable of being reduced. This formulation is then pseudo-first order with respect to the donor molecule and driven largely to thermodynamic equilibrium by the concentration of peroxidase.
In general the preparation used for cold sterilization of contact lenses should have maximum concentration levels of about 0.1 milligram per ml for the enzyme, 0.1 milligram per ml for the donor molecule and 0.03% for hydrogen peroxide.